A process for preparation of 3,6-dichlorocyano pyrazine, 3,6-dioxopiperazine derivatives and production of favipiravir thereof

Abstract

The present disclosure provides a process for preparation of 3,6-dichlorocyano pyrazine, 3,6-dioxopiperizine derivatives and production of favipiravir via ammonia or amine-mediated cyclization and chlorination using POCl3 in the presence of pyridine or PCl5. [Formula] wherein in 3,6-dioxopiperazine derivatives (III), X is CN, CONH2 or COOR2′, R1, R2 and R2′ are individually selected from H, C1-C12 alkyl, COOR3 and SO2R3 wherein R3 is substituted or unsubstituted linear or branched lower alkyl.

We claim: 
     
         1 . A process for preparation of 3,6-dichlorocyano pyrazine of formula II, 
       
         
           
           
               
               
           
         
         comprising the steps of: 
         (a) chlorination of 3,6-dioxopiperazine derivative of formula III with POCl 3  and pyridine or PCl 5  at a temperature in the range of 90-140° C. for 4-20 hours, 
       
       
         
           
           
               
               
           
         
         
           wherein X is CN, CONH 2  or COOR 2 ′, R 1 , R 2  and R 2 ′ are individually selected from H, C1-C12 alkyl, COOR 3  and SO 2 R 3  wherein R 3  is substituted or unsubstituted linear or branched lower alkyl, to obtain a compound of Formula II and 
         
         (b) purification of the compound of Formula II obtained in step (a). 
       
     
     
         2 . The process as claimed in  claim 1 , wherein the purification method is selected from crystallization, filtration, and chromatography. 
     
     
         3 . A process for preparation of 3,6-dioxopiperazine derivatives of formula III, 
       
         
           
           
               
               
           
         
         wherein, X is CN, CONH 2  or COOR 2 ′, R 1 , R 2  and R 2 ′ are individually selected from H, C1-C12 alkyl, COOR 3  and SO 2 R 3  wherein R 3  is substituted or unsubstituted linear or branched lower alkyl, comprising the steps of: 
       
       (a) cyclization of halo-amide of formula V 
       
         
           
           
               
               
           
         
         wherein X′ and Y′ are individually selected from CN, CONH 2  and COOR 3 ′, where R 3 ′ is selected from H and C1-C12 alkyl, A is selected from Cl, Br, OH and OR 5  wherein R 5  is SO 2 R 4  and R 4  is substituted or unsubstituted linear or branched lower alkyl, 
         with alcoholic ammonia or amine derivative at a temperature in the range of 60-100° C. for 10-24 hours to obtain a compound of Formula III, and 
       
       (b) filtration and recrystallization of the compound of Formula III obtained in step (a). 
     
     
         4 . The process as claimed in  claim 3 , wherein the alcoholic ammonia is methanolic ammonia, or ethanolic ammonia; and the amine derivative is selected from alkyl, cycloalkyl, or benzyl amines, carbamates, and sulphonamides. 
     
     
         5 . The process as claimed in  claim 3 , wherein the recrystallization is carried out in a solvent system selected from alcohol as a single solvent, or a two solvent mixtures, comprising a water:alcohol system. 
     
     
         6 . The process as claimed in  claim 3 , wherein the halo-amide of formula V 
       
         
           
           
               
               
           
         
         wherein X′ and Y′ are individually selected from CN, CONH 2  and COOR 3 ′, where R 3 ′ is selected from H and C1-C12 alkyl, A is selected from Cl, Br, OH and OR 5  wherein R 5  is SO 2 R 4  and R 4  is substituted or unsubstituted linear or branched lower alkyl, is prepared by acylation reaction between the compound of formula IV and chloroacetyl chloride of formula VI in presence of base at room temperature, 
       
       
         
           
           
               
               
           
         
         wherein X′ and Y′ are as defined above; 
       
       
         
           
           
               
               
           
         
         wherein A is as defined above and B is selected from Cl, Br, OH and OR 5  wherein R 5  is SO 2 R 4  and R 4  is substituted or unsubstituted linear or branched lower alkyl. 
       
     
     
         7 . A process for preparation of 3,6-dichlorocyano pyrazine of formula II 
       
         
           
           
               
               
           
         
         which comprises the steps of: 
         (a) acylation reaction between the compound of formula IV and chloroacetyl chloride of formula VI in presence of base at room temperature to obtain halo-amide of formula V, 
       
       
         
           
           
               
               
           
         
         
           wherein X′ and Y′ are individually selected from CN, CONH 2  and COOR 3 ′, where R 3 ′ is selected from H and C1-C12 alkyl, A is selected from Cl, Br, OH and OR 5  wherein R 5  is SO 2 R 4  and R 4  is substituted or unsubstituted linear or branched lower alkyl, 
         
       
       
         
           
           
               
               
           
         
         
            wherein X′ and Y′ are as defined above; 
         
       
       
         
           
           
               
               
           
         
         
            wherein A is as defined above and B is selected from Cl, Br, OH and OR 5  wherein R 5  is SO 2 R 4  and R 4  is substituted or unsubstituted linear or branched lower alkyl; 
         
         (b) cyclization of halo-amide of formula V with alcoholic ammonia or amine derivative, at a temperature in the range of 60-100° C. for 10-24 hours to obtain a compound of Formula III, 
       
       
         
           
           
               
               
           
         
         
           wherein, X is CN, CONH 2  or COOR 2 ′, R 1 , R 2  and R 2 ′ are individually selected from H, C1-C12 alkyl, COOR 3  and SO 2 R 3  wherein R 3  is substituted or unsubstituted linear or branched lower alkyl, 
         
         (c) chlorination of 3,6-dioxopiperazine derivative of formula III with POCl 3  and pyridine or PCl 5  at a temperature in the range of 90-140° C. for 4-20 hours, to obtain a compound of Formula II and 
         (d) purification of the compound of Formula II. 
       
     
     
         8 . The process as claimed in  claim 7 , wherein the alcoholic ammonia is methanolic ammonia, or ethanolic ammonia; the amine derivative is selected from alkyl, cycloalkyl, or benzyl amines, carbamates, and sulphonamides; and the purification method is selected from crystallization, filtration, and chromatography. 
     
     
         9 . A process for preparation of compound of formula I 
       
         
           
           
               
               
           
         
       
       which comprises the steps of:
 (a) cyclization of halo-amide of formula V 
 
       
         
           
           
               
               
           
         
         
           wherein X′ and Y′ are individually selected from CN, CONH 2  and COOR 3 ′, where R 3 ′ is selected from H and C1-C12 alkyl, A is selected from Cl, Br, OH and OR 5  wherein R 5  is SO 2 R 4  and R 4  is substituted or unsubstituted linear or branched lower alkyl, 
         
         with alcoholic ammonia or amine derivatives at a temperature in the range of 60-100° C. for 10-24 hours to obtain a compound of Formula III, 
       
       
         
           
           
               
               
           
         
         wherein, X is CN, CONH 2  or COOR 2 ′, R 1 , R 2  and R 2 ′ are individually selected from H, C1-C12 alkyl, COORS and SO 2 R 3  wherein R 3  is substituted or unsubstituted linear or branched lower alkyl, 
         (b) chlorination of 3,6-dioxopiperazine derivative of formula III with POCl 3  and pyridine or PCl 5  at a temperature in the range of 90-140° C. for 4-20 hours, to obtain a compound of Formula II; 
       
       
         
           
           
               
               
           
         
         (c) fluorination of compound of formula II obtained in step (b) with potassium fluoride and PTC in a solvent to obtain difluorocyano pyrazine of formula VII at a temperature in the range of 50° C. to 70° C.; 
       
       
         
           
           
               
               
           
         
         (d) functionalization of aromatic ring in the compound of formula VII obtained in step (c) from fluorine to hydroxy in the presence of sodium acetate to obtain 6-fluoro-3-hydroxypyrazine-2-carbonitrile of formula VIII; 
       
       
         
           
           
               
               
           
         
          and 
         (e) hydrolysis of cyano functionality of formula VIII to amide in presence of H 2 O 2  and NaOH solution to obtain compound of formula I. 
       
     
     
         10 . The process as claimed in  claim 9 , wherein the alcoholic ammonia is methanolic ammonia, or ethanolic ammonia; the amine derivative is selected from alkyl, cycloalkyl, or benzyl amines, carbamates, and sulphonamides; and the solvent used in step (c) is selected from DMF, and DMSO.